Chemical screening identifies novel small molecule activators of natural killer cell cytotoxicity against cancer cells

Cancer Immunol Immunother. 2022 Jul;71(7):1671-1680. doi: 10.1007/s00262-021-03117-w. Epub 2021 Nov 23.

Abstract

Natural killer (NK) cells are cytotoxic lymphocytes that play a major role in the innate immune system. NK cells exhibit potent cytotoxic activity against cancer cells and virally infected cells without antigen priming. These unique cytotoxic properties make NK cells a promising therapeutic against cancer. Limitations of NK cell therapy include deficiencies in high clinical efficacy often due to a need for a high NK cell to target cell ratio to achieve effective killing. In order to address the suboptimal efficacy of current adoptive NK cell therapy, a high throughput screen (HTS) was designed and performed to identify drug-like compounds that increase NK cytotoxic activity against tumor cells without affecting the normal cells. This screen was performed in a 384-well plate format utilizing an expanded primary NK cell product and ovarian cancer cells as a target cell (TC) line. Of the 8000 diverse small molecules screened, 16 hits were identified (0.2% hit rate) based on both a robust Z (RZ) score < -3 and a greater than 10% increase in NK cell killing. A validation screen had a confirmation rate of 70%. Select compounds were further validated and characterized by additional cytotoxicity assays including activity against multiple blood cancer and solid tumor cell lines, with no effect on primary human T cells. This work demonstrates that high-throughput screening can be reliably used to identify compounds that increase NK tumoricidal activity in vitro that can be further investigated and translated for potential clinical application. Précis: Our work led to the identification of promising compound that potently increases NK cell-mediated killing of a variety of different cancer cells, but no impact on the killing of normal cells. This compound demonstrates the utility of this assay.

Keywords: High-throughput screen; Immunotherapy; NK activation; NK cells; NK cytotoxicity; Ovarian cancer.

MeSH terms

  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Early Detection of Cancer*
  • Humans
  • Immunotherapy, Adoptive
  • Killer Cells, Natural
  • Neoplasms* / drug therapy
  • Neoplasms* / metabolism
  • T-Lymphocytes